RNA biomarkers for alcohol use disorder

酒精使用障碍的 RNA 生物标志物

• 批准号: 10808532
• 负责人: Laura Brockway Ferguson
• 金额: $ 13.55万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10808532
• 关键词: Address; Aftercare; Air; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Area; Award; Behavior assessment; Biological; Biological Assay; Biological Markers; Biometry; Blood; Blood Tests; Blood specimen; Brain; Caring; Chronic; Classification; Clinical; Clinical Management; Clinical Trials; Clinical assessments; Data; Development; Diagnosis; Diagnostic; Digoxin; Disease Management; Disease Progression; Drug Prescriptions; Escalator; Ethanol; Ethics; Event; Experimental Designs; Exposure to; Foundations; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Health Personnel; Heavy Drinking; Heterogeneity; Human; Individual; Institutional Review Boards; Joints; Knowledge; Medical; Messenger RNA; Methods; Modeling; Molecular; Monitor; Mus; Naltrexone; Observational Study; Outcome; Pathway interactions; Patient Monitoring; Patients; Pharmacologic Substance; Pharmacotherapy; Physicians; Population; Prediction of Response to Therapy; Process; Prognosis; Proxy; Publishing; RNA; Regulator Genes; Research; Risk; Rodent; Sampling; Screening procedure; Selection for Treatments; Solid; Specimen; Techniques; Technology; Testing; Therapeutic; Time; Training; Withdrawal; Work; alcohol availability; alcohol exposure; alcohol research; alcohol risk; alcohol seeking behavior; alcohol use disorder; brain tissue; design; differential expression; drinking; experience; experimental analysis; experimental study; forest; genomic profiles; human subject; improved; infancy; insight; longitudinal analysis; minimally invasive; model building; molecular marker; mouse model; next generation sequencing; optimal treatments; patient population; patient stratification; personalized medicine; potential biomarker; precision medicine; predicting response; predictive marker; predictive modeling; programs; prospective; protocol development; recruit; responders and non-responders; response; risk prediction; statistics; success; tool; transcriptome; transcriptome sequencing; transcriptomics; translational potential; treatment effect; treatment response; vapor

Next generation sequencing and other -omics technologies have spurred the development of precision medicine, but this field is still in its infancy for alcohol use disorder (AUD). Transcriptomic studies have established that alcohol use causes widespread changes in brain gene expression. Brain gene expression profiles can identify alcohol-dependent human subjects and mice and can be used to repurpose pharmaceuticals that reduce excessive alcohol consumption in rodents. However, it is not possible to obtain brain samples from living patients, which limits the translational potential of this approach. Routine blood testing has long been a part of medical care. Blood genomic profiles could potentially be used to non-invasively determine whether a patient is at risk for AUD, provide data-driven diagnosis of AUD, stratify the heterogeneous AUD patient population for clinical trials, select optimal therapy, and monitor treatment response and disease progression. As a first step toward these goals, Dr. Ferguson analyzed gene expression patterns in paired blood and brain samples from mice subjected to chronic intermittent ethanol (CIE) exposure, a mouse model of alcohol dependence. Blood gene expression signatures of CIE predicted a pharmaceutical that reduced alcohol drinking in mice, and predictive models built from blood profiles distinguished between CIE and air-exposed mice with high accuracy. These results lead to the hypothesis that blood can serve as a proxy for brain tissue in molecular-based diagnostic or therapeutic tools and advance personalized medicine approaches for AUD. However, it is not known whether there is a biological signature of AUD in blood from a human population. Furthermore, there is a need for biomarkers to predict and monitor treatment success and it is unknown whether blood gene expression profiles might be useful in this regard. The CIE blood signature used in the previous study assayed the transcriptome only at a single time point. Therefore, the dynamics or ongoing transition of important gene regulatory functions were not investigated. These gaps in knowledge will be addressed in proposed Aims by analyzing blood profiles (1) across multiple time points throughout alcohol withdrawal in humans (Aim 1), (2) across multiple time points through the development of CIE-induced alcohol dependence in mice (Aim 2), and (3) before and after treatment in humans and mice (Aim 3). The overarching hypothesis is that genomic profiles from blood will improve the clinical management of AUD including diagnosis, prognosis, and predicting treatment response. These Aims and the accompanying training plan were designed to build on Dr. Ferguson’s previous research experiences and facilitate new scientific training in clinical alcohol research and biostatistical analyses of longitudinal data, time-to-event outcome data, and treatment effect estimation. The proposed Pathway to Independence Award will generate new knowledge about a relatively unstudied area in alcohol research and enable Dr. Ferguson to establish a solid framework for building a successful research program as an academic translational neuroscientist in the alcohol field.

下一代测序和其他组学技术刺激了精准度的发展 医学，但该领域对于酒精使用障碍（AUD）的转录组学研究仍处于起步阶段。 确定饮酒会导致大脑基因表达的广泛变化。 配置文件可以识别酒精依赖的人类受试者和小鼠，并可用于重新调整用途 然而，目前还无法获得减少啮齿类动物过度饮酒的药物。 来自活体患者的脑样本，这限制了这种方法的转化潜力。 血液基因组检测长期以来一直是医疗保健的一部分，有可能用于非侵入性治疗。 确定患者是否有 AUD 风险，提供数据驱动的 AUD 诊断，对患者进行分层 异质 AUD 患者群体进行临床试验、选择最佳治疗并监测治疗 作为实现这些目标的第一步，弗格森博士分析了基因表达。 慢性间歇性乙醇（CIE）暴露小鼠的配对血液和脑样本的模式， 酒精依赖的小鼠模型预测了 CIE 的药物基因表达特征。 减少了小鼠的饮酒量，并根据血液特征建立的预测模型区分了 CIE 和暴露于空气中的小鼠具有很高的准确性，这些结果得出了血液可以作为一种物质的假设。 在基于分子的诊断或治疗工具中替代脑组织并推进个性化医疗 然而，尚不清楚来自 AUD 的血液中是否存在 AUD 的生物特征。 此外，需要生物标志物来预测和监测治疗的成功与否。 尚不清楚血液基因表达谱在这方面是否有用。 先前研究中使用的转录组仅在单个时间点进行测定，因此，动态或。 重要基因调控功能的持续转变并未得到研究。 在提议的目标中通过分析酒精中多个时间点的血液特征 (1) 来解决 通过发展 CIE-酒精诱导的人类戒断（目标 1）、（2）跨越多个时间点 小鼠的依赖性（目标 2），以及（3）人类和小鼠治疗前后的依赖性（目标 3）。 假设来自血液的基因组图谱将改善 AUD 的临床管理，包括 诊断、预后和预测治疗反应这些目标以及随附的培训计划。 旨在以弗格森博士之前的研究经验为基础，并促进新的科学培训 临床酒精研究和纵向数据、事件时间结果数据的生物统计分析，以及 拟议的独立之路奖将产生新的知识。 关于酒精研究中相对未被研究的领域，并使弗格森博士能够建立一个坚实的框架 作为酒精领域的学术转化神经科学家，建立了一个成功的研究项目。